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PubMed1971

The hydrolysis by thermolysin of dipeptide derivatives that conatin substituted cysteine.

1. The preparation of protected dipeptides of the form acetylglycylamino acid amides is described, where the amino acid is phenylalanine, leucine, valine, alanine, S-methylcysteine, S-ethylcysteine, S-benzylcysteine and S-phenylcysteine. 2. Kinetic parameters for the thermolytic hydrolysis of these blocked dipeptides are reported. The rate of hydrolysis was fastest when the amino acid was leucine or phenylalanine, slower when it was S-methylcysteine, valine or S-ethylcysteine, much slower when it was alanine, and negligible for S-phenylcysteine or S-benzylcysteine. 3. The results are compared with those for similar dipeptide derivatives with benzyloxycarbonyl and furylacryloyl blocking groups, which are hydrolysed faster.

Alanine↗
PubMed1977

Solvent accessibilities in glycyl, alanyl and seryl dipeptides.

Theoretical studies on glycyl-alanyl and seryl dipeptides were performed to determine the probable backbone and side-group conformations that are preferred for solvent interaction. By following the method of Lee & Richards [(1971) J. Mol. Biol. 55, 379-400], a solute molecule is represented by a set of interlocking spheres of appropriate van der Waals radii assigned to each atom, and a solvent (water) molecule is rolled along the envelope of the van der Waals surface, and the surface accessible to the solvent molecule, and hence the solvent accessibility for a particular conformation of the solute molecule, is computed. From the calculated solvent accessibilities for various conformations, solvation maps for dipeptides were constructed. These solvation maps suggest that the backbone polar atoms could interact with solvent molecules selectively, depending on the backbone conformation. A conformation in the right-handed bridge (zetaR) region is favoured for both solvent interaction and intrachain hydrogen-bonding. Also the backbone side-chain hydrogen-bonding within the same dipeptide fragment in proteins is less favoured than hydrogen-bonding between side chain and water and between side chain and atoms of other residues. Solvent accessibilities suggest that very short distorted alphaR-helical and extended-structural parts may be stabilized via solvent interaction, and this could easily be possible at the surface of the protein molecules, in agreement with protein-crystal data.

Alanine↗
PubMed1983

New class of sensitive and selective fluorogenic substrates for serine proteinases. Amino acid and dipeptide derivatives of rhodamine.

A series of dipeptide derivatives of Rhodamine, each containing an arginine residue in the P1 position and one of ten representative benzyloxycarbonyl (Cbz)-blocked amino acids in the P2 position, has been synthesized, purified and characterized as substrates for serine proteinases. These substrates are easily prepared with high yields. Cleavage of a single amide bond converts the non-fluorescent bisamide substrate into a highly fluorescent monoamide product. Macroscopic kinetic constants for the interaction of these substrates with bovine trypsin, human and dog plasmin, and human thrombin are reported. Certain of these substrates exhibit extremely large specificity constants. For example, the kcat./Km for bovine trypsin with bis-(N-benzyloxycarbonylglycyl-argininamido)-Rhodamine [(Cbz-Gly-Arg-NH)2-Rhodamine] is 1 670 000 M-1 X S-1. Certain of these substrates are also highly selective. For example, the most specific substrate for human plasmin, (Cbz-Phe-Arg-NH2)-Rhodamine, is not hydrolysed by human thrombin, and the most specific substrate for human thrombin, (Cbz-Pro-Arg-NH)2-Rhodamine, is one of the least specific substrates for human plasmin. Comparison of the kinetic constants for hydrolysis of the dipeptide substrates with that of the single amino acid derivative, (Cbz-Arg-NH)2-Rhodamine, indicates that selection of the proper amino acid residue in the P2 position can effect large increases in substrate specificity. This occurs primarily as a result of an increase in kcat. as opposed to a decrease in Km and, in certain cases, is accompanied by a large increase in selectivity. Because of their high degree of sensitivity and selectivity, these Rhodamine-based dipeptide compounds should be extremely useful substrates for studying serine proteinases.

Amino Acids↗
PubMed1977

Metabolism of intravenously administered dipeptides in rats: effects on amino acid pools, glucose concentration and insulin and glucagon secretion.

1. Studies were performed to investigate the metabolic fate of dipeptides when administered intravenously in rats. Glycyl-leucine, glycylglycine or glycylsarcosine was injected into the jugular vein. The plasma disappearance rate after the peak plasma concentrations was most rapid for glycyl-leucine and least rapid for glycylsarcosine. 2. During urine collection for 40 min, trace amounts of glycyl-leucine and glycylglycine and 13% of the injected glycylsarcosine were excreted. 3. Neither glycylglycine nor glycyl-leucine was detected in the liver, muscle, intestinal mucosa or renal cortex, but concentrations of glycine or leucine, or both, in these tissues were increased after each injection. In contrast, glycylsarcosine was recovered in all these tissues with concentrations in the renal cortex being far greater than in any other tissue, but sarcosine was found only in the renal cortex and intestinal mucosa. 4. The changes in plasma concentrations of free amino acids, glucose and glucagon, and tissue concentrations of free amino acids, were similar after the intravenous administration of glycyl-leucine and an equimolar mixture of free glycine and leucine. However, the amount of insulin secreted during the 40 min after glycyl-leucine injection was 1-6 times that produced after the injection of the corresponding amino acid mixture. 5. Results show that, within the present experimental conditions, the intravenous administration of dipeptides is as effective as that of the corresponding free amino acids in enriching the tissue pools of amino acids. It is suggested that efficient hydrolysis by cellular enzymes prohibits accumulation of intact dipeptides in body tissues.

Amino Acids↗
PubMed2005

Influence of vibrational energy flow on isomerization of flexible molecules: incorporating non-Rice-Ramsperger-Kassel-Marcus kinetics in the simulation of dipeptide isomerization.

The conformational isomerization of a dipeptide, N-acetyl-tryptophan methyl amide (NATMA), is studied computationally by including important dynamical corrections to Rice-Ramsperger-Kassel-Marcus (RRKM) theory for the transition rate between pairs of isomers. The dynamical corrections arise from incomplete or sluggish vibrational energy flow in the dipeptide, a property suggested by the mode-selective chemistry that has been observed by Dian et al. [J. Chem. Phys. 120, 133 (2004)]. We compute the extent and rate of vibrational energy flow in NATMA quantum mechanically using local random matrix theory, which we then use to correct the RRKM theory rates. The latter rates are then introduced into a master equation to study the population dynamics of the dipeptide. Incomplete or slow vibrational energy flow is found to enhance the conformational selectivity of NATMA over RRKM estimates.

Chemistry, Physical↗
PubMed2002

Pairs of dipeptides synergistically activate the binding of substrate by ubiquitin ligase through dissociation of its autoinhibitory domain.

Protein degradation by the ubiquitin (Ub) system controls the concentrations of many regulatory proteins. The degradation signals (degrons) of these proteins are recognized by the system's Ub ligases (complexes of E2 and E3 enzymes). Two substrate-binding sites of UBR1, the E3 of the N-end rule pathway in the yeast Saccharomyces cerevisiae, recognize basic (type 1) and bulky hydrophobic (type 2) N-terminal residues of proteins or short peptides. A third substrate-binding site of UBR1 targets CUP9, a transcriptional repressor of the peptide transporter PTR2, through an internal (non-N-terminal) degron of CUP9. Previous work demonstrated that dipeptides with destabilizing N-terminal residues allosterically activate UBR1, leading to accelerated in vivo degradation of CUP9 and the induction of PTR2 expression. Through this positive feedback, S. cerevisiae can sense the presence of extracellular peptides and react by accelerating their uptake. Here, we show that dipeptides with destabilizing N-terminal residues cause dissociation of the C-terminal autoinhibitory domain of UBR1 from its N-terminal region that contains all three substrate-binding sites. This dissociation, which allows the interaction between UBR1 and CUP9, is strongly increased only if both type 1- and type 2-binding sites of UBR1 are occupied by dipeptides. An aspect of autoinhibition characteristic of yeast UBR1 also was observed with mammalian (mouse) UBR1. The discovery of autoinhibition in Ub ligases of the UBR family indicates that this regulatory mechanism may also control the activity of other Ub ligases.

Amino Acid Sequence↗
PubMed1971

Initial dipeptide formation in hemoglobin biosynthesis.

Initiation factors M(1) + M(2) from reticulocyte ribosomes bind Met-tRNA(F) to rabbit reticulocyte ribosomes containing endogenous hemoglobin mRNA. The initial binding of Met-tRNA(F) appears to be to the small ribosomal subunit. The Met-tRNA(F) is able to participate in what is presumed to be the first peptide bond in the formation of hemoglobin, namely the synthesis of a methionyl-valine dipeptide. The formation of this methionyl-valine dipeptide requires Met-tRNA(F), initiation factors M(1), M(2), and M(3), as well as Val-tRNA and T(1). No synthesis of methionyl-valine dipeptide takes place if Met-tRNA(F) is replaced by Met-tRNA(M), or if initiation factor M(3) is omitted. Thus, Met-tRNA(F) appears to be the initiator tRNA for hemoglobin biosynthesis and M(3), although required for the synthesis of the first peptide bond of hemoglobin, does not appear to be necessary, under the experimental conditions studied, for Met-tRNA(F) binding.

Animals↗
PubMed1977

Transition state structures of a dipeptide related to the mode of action of beta-lactam antibiotics.

The tetrahedral adducts formed during nucleophilic attack by a hydroxyl ion on the carbonyl carbon of a model dipeptide, glycylglycine, were studied by modified-intermediate-neglect-of-differential-overlap molecular orbital calculations. This dipeptide is taken to represent the D-alanyl-D-alanine terminus of the polypeptides involved in the cross-linking transpeptidation reaction of peptidoglycan in bacterial cell walls. It was found that nucleophilic attack on one face of the carbonyl carbon leads to a transition intermediate species structurally similar to that afforded by the bicyclic nucleus of penicillins and cephalosporin antibiotics. The results support the concept that the beta-lactam antibiotics, which are known to inhibit various bacterial cell wall enzymes, may act as transition state analogs. Also, the structure formed from nucleophilic attack on the so-called alpha face of the dipeptide is more similar to the antibiotic structures than is that from attack on the opposite face. In agreement with other types of experiments, the results suggest that the alpha face may be the one approached by a nucleophile in the receptor site(s) of the appropriate cell wall enzymes.

Cephalosporins↗
PubMed1978

A model for hydration of peptides and its application to the conformational analysis of terminally blocked amino acids and dipeptides.

A theoretical model for peptide structure, which takes into account the effects of hydration in conformational energy calculations, is described. The free energy of hydration is composed of a term for "specific hydration," representing solute-water hydrogen bonding, and a term for "non-specific hydration," describing the interaction of the solute with water molecules in a first-neighbor shell. Minimum-energy conformations were computed for the hydrated N-acetyl-N'-methylamides of the 20 naturally occurring amino acids, and the results were compared with those computed in the absence of hydration. The relative energies of many conformations and the width of some low-energy regions of the (ø, Psi) conformational maps are altered when the free energy of nonspecific hydration is included. The term for specific hydration causes large charges of the energy, but only in some regions of the maps. Observed vicinal coupling constants are approximated better by the computation when hydration is included. Conformational preferences of the individual residues in hydrated dipeptides are similar to those computed for the hydrated single residues, showing that intraresidue interactions predominate in dipeptides. This supports the concept of the importance of short-range interactions in proteins. Bend probabilities were computed and compared with observed frequencies of occurrence of bends in proteins of known structure. Computed values improve only for some of the dipeptides containing polar residues or glycine when hydration is included. For bends involving two nonpolar residues, computations omitting hydration give better results.

Amino Acid Sequence↗
PubMed1982

In vitro synthesis of the first dipeptide of the beta subunit of Escherichia coli RNA polymerase.

Plasmids pNF1337 and pNF1341, which contain part of the L10 operon including the RNA polymerase beta-subunit gene, have been used as templates in vitro to investigate expression of the beta-subunit gene. For these studies, the synthesis of the first dipeptide of the beta subunit, fMet-Val, was measured instead of that of the entire protein. By using this dipeptide system, we studied the effects of RNA polymerase holoenzyme and L factor (nus A gene product) on fMET-Val synthesis and compared the relative effects of the primary and secondary promoters in the L10 operon on expression of the beta-subunit gene. The results show that the inhibitory effect of RNA polymerase on beta-subunit synthesis and the stimulatory effect of L factor occur before formation of the first dipeptide bond. In this in vitro system, the secondary promoters account for about 50% of the total fMet-Val synthesized. Although the primary promoter is sensitive to guanosine 5'-diphosphate 3'-diphosphate in vitro, the secondary promoters are not affected by this nucleotide.

Bacterial Proteins↗
PubMed1997

The conserved serine-tyrosine dipeptide in Leishmania donovani hypoxanthine-guanine phosphoribosyltransferase is essential for catalytic activity.

Crystal structures of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) proteins have implied that the translocation of a flexible loop containing a highly conserved Ser-Tyr dipeptide is necessary for the protection of the proposed oxocarbonium ion transition state of the enzyme (Eads, J. C., Scapin, G. T., Xu, Y., Grubmeyer. C., and Sacchettini, J. C. (1994) Cell 78, 325-334; Schumacher, M. A., Carter, D., Roos, D. S., Ullman, B., and Brennan, R. G. (1996) Nature Struct. Biol. 3, 881-887). An essential role for this Ser-Tyr dyad in HGPRT catalysis has now been verified biochemically and genetically for the Leishmania donovani HGPRT employing a combination of protein modifying reagents and site-directed mutagenesis. Incubation of HGPRT with either tetranitromethane or diethyl pyrocarbonate inactivated the enzyme completely, and peptide sequence analysis revealed that tetranitromethane treatment modified the Tyr residue within the Ser95-Tyr96 dipeptide. Analysis of site-directed mutants confirmed that both amino acids were vital for phosphoribosylation activity. Mutant HGPRTs, S95A, S95E, Y96F, and Y96V, exhibited dramatic reductions in their catalytic capabilities of 2-3 orders of magnitude, whereas HGPRTs containing conservative substitutions, S95C and S95T, displayed only a 2-3-fold decrease in kcat. Km values for the substrates of the forward and reverse reactions were largely unchanged for all HGPRT constructs, except for a 4-5-fold decrease in the Km value of the Y96F and Y96V mutants for phosphoribosylpyrophosphate. Expression of L. donovani hgprt constructs in Escherichia coli indicated that wild type and S95T HGPRTs complemented bacterial phosphoribosyltransferase deficiencies, whereas the S95A and S95C mutants complemented weakly, and the S95E, Y96F, and Y96V HGPRT did not support bacterial growth. These data authenticate that the Ser-Tyr dipeptide that is conserved among all members of the HGPRT family is essential for phosphoribosylation of purine nucleobases by HGPRT.

Amino Acid Sequence↗
PubMed1980

E.s.r. of spin-trapped radicals in gamma-irradiated polycrystalline amino acids, N-acetyl amino acids and dipeptides.

The radicals produced in several polycrystalline amino acids, N-acetyl amino acids and dipeptides by gamma-radiolysis at room temperature were investigated by spin-trapping. After irradiation in the solid state, the samples were dissolved in aqueous solutions f t-nitrosobutane and the trapped radicals identified by e.s.r. For alpha-amino acids, deamination radicals were found, and in some cases H-abstraction radicals were also observed. No decarboxylation radicals could be detected. For N-acetyl amino acids, except for N-acetylglycine, the major radical was the decarboxylation radical. For N-acetyglycine the H-abstraction radical from the glycine residue was observed. For dipeptides of the x-glycine, the radical formed by removal of H from the alpha-carbon of the carboxyl-terminal residue was always spin-trapped. Some primary deamination radicals and minor amounts of decarboxylation radicals could also be observed. For dipeptides of the type x-alanine, glycine-x and alanine-x, the decarboxylation radical was always the major spin-trapped radical. Some primary and secondary deamination radicals were also detected.

Amino Acids↗
PubMed2006

Alcalase-catalyzed, kinetically controlled synthesis of a precursor dipeptide of RGDS in organic solvents.

The protease-catalyzed, kinetically controlled synthesis of a precursor dipeptide of RGDS, Z-Asp-Ser-NH2 in organic solvents was studied. Alcalase, an industrial alkaline protease, was used to catalyze the synthesis of the target dipeptide in water-organic cosolvents systems with Z-Asp-OMe as the acyl donor and Ser-NH2 as the nucleophile. Acetonitrile was selected as the organic solvent from acetonitrile, ethanol, methanol, DMF, DMSO, ethyl acetate, 2-methyl-2-propanol, and chloroform tested under the experimental conditions. The conditions of the synthesis reaction were optimized by examining the effects of several factors, including water content, temperature, pH, and reaction time on the Z-Asp-Ser-NH2 yields. The optimum conditions are pH 10.0, 35 degrees C, in acetonitrile/Na2CO3-NaHCO3 buffer system (85:15, v/v), 6 h, with a dipeptide yield of 75.5%.

Acetonitriles↗
PubMed2006

Designed aromatic homo-dipeptides: formation of ordered nanostructures and potential nanotechnological applications.

Molecular self-assembly offers new routes for the fabrication of novel materials at the nano-scale. Peptide-based nanostructures represent nano-objects of particular interest, as they are biocompatible, can be easily synthesized in large amounts, can be decorated with functional elements and can be used in various biological and non-biological applications. We had previously revealed the formation of highly ordered tubular structures by the diphenylalanine peptide, the core recognition motif of Alzheimer's beta-amyloid polypeptide, due to specific aromatic interactions. We further confirmed this model and demonstrated that a non-charged peptide analogue, Ac-Phe-Phe-NH2, self-assembled into similar tubular structures. We later explored other amine and carboxyl modified diphenylalanine peptide analogues and revealed that these dipeptides can form ordered tubular structures at the nanometric scale. Moreover, a very similar peptide, the diphenylglycine, self-assembled into ordered nano-spherical assemblies. Here we extend our research and explore the self-assembly of other homo-aromatic dipeptides in which their phenyl side-chains are modified with halogen atoms (di-para-fluoro-Phe, di-pentafluoro-Phe, di-para-iodo-Phe), additional phenyl groups (di-4-phenyl-Phe), or with nitro substitutions (di-para-nitro-Phe). We also probed the effect of the alteration of the phenyl groups with naphtyl groups (di-D-1-Nal and di-D-2-Nal). In all cases, well-ordered nanostructures were obtained and studied by scanning electron microscopy, transmission electron microscopy and vibrational spectroscopy. Taken together, the current work and previous ones define the homo-aromatic dipeptide as a central motif for the formation of ordered self-assembled tubular, spherical and two-dimensional structures at the nano-scale.

Amino Acid Sequence↗
PubMed1993

Classification of protein sequences by their dipeptide composition.

A simple approach to scan quickly a large protein sequence database for homology is described. The approach used is strictly dependent on the database organization. A database has been compiled in which protein sequences are grouped into families of closely related proteins, each family being characterized by its average dipeptide composition. A new entry in the database can be allocated in a family by comparing its dipeptide composition with the average dipeptide composition of the families.

Algorithms↗
PubMed2000

The pharmacokinetic responses of humans to 20 g of alanyl-glutamine dipeptide differ with the dosing protocol but not with gastric acidity or in patients with acute Dengue fever.

Pharmacokinetic responses to oral doses of the dipeptide, L-alanyl-glutamine (Ala-Gln), were evaluated after a single, bolus load or an intermittent dosing in normal healthy subjects (n = 8) to find the optimal mode of oral administration. In a subgroup (n = 4) of the healthy subjects, the influence of a gastric acid suppressor (Omeprazole) was investigated. The influence of an acute episode of classic Dengue fever was examined in eight patients. All modes of administration to healthy subjects significantly increased free plasma Gln and alanine concentrations. Peak increments of plasma Gln concentration were 794+/-107 micromol/L (mean +/- SEM) after bolus intake of 20 g of Ala-Gln and 398+/-61 micromol/L after intermittent intake of the same cumulative dosage of the dipeptide (P<0.01). After intermittent dosing, the maximum peak increase appeared significantly later (P<0.01). Areas under the curve (AUC), expressing the integrated responses over time of plasma free Gln and alanine concentrations, did not differ after bolus and intermittent loads of Ala-Gln. Pretreatment with the acid suppressor, Omeprazole, did not influence Gln (P = 0.79) or alanine (P = 0.90) plasma increment. Dengue patients manifested the same pharmacokinetic responses to a 20 g Ala-Gln bolus as healthy controls. In general, on a micromolar concentration basis, Gln and alanine followed parallel tracks in terms of plasma appearance, clearance and elimination after the oral administration of 20 g of the Ala-Gln dipeptide through the range of conditions and dosing protocols explored here.

Administration, Oral↗
PubMed2005

Alanylglutamine dipeptide and growth hormone maintain PepT1-mediated transport in oxidatively stressed Caco-2 cells.

Reactive oxygen species (ROS) produced by gut mucosal cells during conditions such as inflammatory bowel disease (IBD) may impair mucosal repair and nutrient transport/absorptive function. Absorption of di- and tripeptides in the small intestine and colon is mediated by the H(+)-dependent transporter PepT1, but effects of oxidative stress on di- and tripeptide transport are unknown. We assessed whether exposure to hydrogen peroxide (H(2)O(2)) influences dipeptide transport in human colonic epithelial (Caco-2) cells. Uptake of [(14)C]glycylsarcosine (Gly-Sar) was used to evaluate PepT1-mediated dipeptide transport. Exposure to 1-5 mmol/L H(2)O(2) for 24 h caused a dose-dependent decrease in Gly-Sar transport, which was associated with decreased PepT1 transport velocity (V(max)). Treatment with alanylglutamine (Ala-Gln) or growth hormone (GH) did not alter Caco-2 Gly-Sar transport in the absence of H(2)O(2). However, both Ala-Gln and GH prevented the decrease in dipeptide transport observed with 1 mmol/L H(2)O(2) treatment. Ala-Gln, but not GH, maintained cellular glutathione and prevented the decrease in PepT1 protein expression. Thus, these agents should be further investigated as potential therapies to improve absorption of small peptides in disorders associated with oxidative injury to the gut mucosa.

Biological Transport↗
PubMed2006

The ACE inhibitory dipeptide Met-Tyr diminishes free radical formation in human endothelial cells via induction of heme oxygenase-1 and ferritin.

Food sources such as soybeans and fish contain angiotensin I converting enzyme (ACE) inhibitory peptides with antihypertensive properties. Methionine-tyrosine (Met-Tyr) is an ACE inhibitory dipeptide derived from sardine muscle. The present study investigates the effect of Met-Tyr on the expression of the antioxidant stress proteins, heme oxygenase-1 (HO-1) and ferritin, in endothelial cells derived from the human umbilical vein and their contribution to the decrease in radical formation that occurs under the influence of this dipeptide. Preincubation of endothelial cells with Met-Tyr (10-300 micromol/L) followed by washout markedly diminished subsequently induced NADPH-mediated radical formation. This indirect protection was associated with a significant increase in protein expression of HO-1 and ferritin and abolished by the HO inhibitor zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG). The HO product bilirubin produced antioxidant effects comparable to those of Met-Tyr. Met-Tyr raised HO-1 mRNA levels by enhancing mRNA stability. Antioxidant effects were specific for Met-Tyr and not observed with other methionine-containing dipeptides or ACE inhibitory agents. Our results demonstrate that Met-Tyr protects endothelial cells from oxidative stress via induction of HO-1 and ferritin but independently of its ACE inhibitory properties. This pathway represents a novel, potentially antiatherogenic mechanism of Met-Tyr and dietary proteins releasing Met-Tyr during gastrointestinal digestion.

Angiotensin-Converting Enzyme Inhibitors↗